Retinoids are a class of naturally occurring and synthetic derivatives of vitamin A which function in vivo as regulators of a number of physiological functions including cellular proliferation, cytodifferentiation and embryonal morphogenesis. In rodents, vitamin A deficiency induces epithelial dysplasia in the tracheobronchial tree, whereas in humans, exogenous treatment with retinoids induces terminal differentiation of certain premalignant lesions of the skin, oral mucosa, and uterine cervix. Meyskens, et al, JNCI 86:539 (1994). The class of retinoids includes a number of clinically important compounds such as those shown FIG. 1 which have been shown or hypothesized to have utility in the therapy and prevention of various types of cancer. For example, Hong et al., N. Eng. J. Med. 323: 795-801 (1990) have shown that adjuvant treatment with 13-cis retinoic acid after definitive anti-cancer treatment in patients with carcinoma of the head and neck significantly reduces the incidence of secondary tumors of the aerodigestive tract. Head and neck cancer, like lung cancer, is significantly related to tobacco smoking, and in fact many of the tumors reduced in incidence in the Hong et al. study were lung cancers. Retinoids have produced striking therapeutic results in patients with acute promyelocytic leukemia, doubling the proportion of patients cured of this highly lethal disease. Warrell, et al., NEJM 329:177 (1993) and Soignet et al., Cancer Chemother. Pharmacol. 40 (Suppl.):S25-S29 (1997). Retinoids have also been shown to be effective in the prevention and reversal of certain types of induced hyperplasia and metaplasia in cultured rodent respiratory epithelial. Lasnitzki et al., Cancer Treatment Reports 66: 1375-1380 (1982). Evidence also suggests that all-trans retinoic acid may induce the proliferation of alveolar cells in lungs that have been damaged by fibrosis. Massaro, et al., Nature Med 3:675 (1997). This surprising observation has suggested that retinoids may have important utility for the treatment of patients with pulmonary emphysema. Chemoprevention trials with retinoids have so far been confined to orally administered drugs, which expose the drug to first-pass metabolism in the liver. Moreover, continuous daily treatment with all-trans retinoic acid is associated with a progressive reduction in plasma drug levels, which may further reduce clinical efficacy.
Unfortunately, while retinoids have been shown to provide beneficial effects in the prevention of at least some types of cancer, the therapeutic regiment requires chronic administration. Under these circumstances, substantial systemic toxicity may result, including hepatic dysfunction, skeletal malformations, mucositis, hyperlipidemia, hypertriglyceridemia (possibly leading to accelerated atherosclerosis and pancreatitis), hypercalcemia, birth defects, and skin, liver and central nervous system toxicity. This toxicity has limited the utility of retinoids as therapeutic agents in the prevention of cancer and in the treatment of lung diseases.
Several potential strategies for mitigating the toxicity of retinoids have been considered, including xe2x80x9cdrug holidaysxe2x80x9d, reductions in dosage, and development of naturally occurring or synthetic ligands that bind specific nuclear retinoid receptors. Lotan, R., FASEB J 10: 1031 (1996). However, none of these strategies has yielded a substantial increase in therapeutic index.
For many drugs, organ-specific targeting, including the inhaled route, has been an effective means of drug delivery. In addition to significantly increasing local drug concentrations at the desired site, this route avoids the xe2x80x9cfirst passxe2x80x9d effect that occurs with transport through the liver. Inhalation therapy has proved especially useful for the treatment of lung diseases including asthma, cystic fibrosis, and P. carinii prophylaxis. J Allergy Clin Immun 88(3):451 (1991).
The ability to provide retinoid therapy for extended periods of time without the systemic toxic effects would enable treatment and prevention of various lung diseases including cancer and emphysema.
We have developed a system for administration of retinoids by inhalation to overcome the chronic toxicity problems presented by systemic administration, to increase the local bioavailability of the retinoids and to make retinoid therapy available as an option for the prevention of epithelial cancers and diseases of the respiratory tract, especially those that are associated with tobacco use. Thus, in accordance with the present invention, there is provided a method for treating lung diseases and preventing epithelial cancer of the respiratory tract in an at-risk individual, comprising administering by inhalation to the respiratory tract of the individual an air-borne composition (i.e., an aerosol or finely divided dry powder) comprising a therapeutically effective amount of at least one retinoid. The retinoid is suitably administered with a metered dose aerosol-producing inhaler, in which the retinoid is dissolved in a combination of a pharmaceutically acceptable chlorofluorocarbon propellant and an amine solubilizing agent.